RESUMEN
OBJECTIVE: Optimizing the multimodality treatment of malignant pleural mesothelioma depends on many factors including an adequate chemotherapeutic response. Currently, chemotherapy regimens for patients with mesothelioma are empirically selected. In vitro chemotherapy resistance in human mesothelioma has not been reported. Our goal was to determine the prevalence of drug resistance in a large sample of malignant pleural mesothelioma using a commercially available assay. METHODS: Tumors specimens (n = 203) were cultured for analysis of chemoresistance using the extreme drug resistance assay. Evaluable results were obtained in 168 (168/203 = 83%) specimens. Each specimen was tested with 3 drugs: cisplatin, gemcitabine, and vinorelbine. Drug resistance was characterized as low, intermediate, or extreme. Median age was 64 years (30-85 years). Forty-four (26%) patients received neoadjuvant chemotherapy before sampling and testing. The distribution of histopathologic cell types was epithelial (103; 61%), mixed (57; 34%), and sarcomatoid (8; 5%). RESULTS: A significant proportion of tumors had extreme/intermediate drug resistance to cisplatin (27%), gemcitabine (31%), or vinorelbine (59%). Nineteen tumors (11%) had extreme/intermediate resistance to all 3 drugs. Resistance (extreme/intermediate) to cisplatin was more prevalent in epithelial tumors than in nonepithelial (33% vs 18%; P = .0394). No significant differences in chemoresistance were found in tumors of patients who had received neoadjuvant chemotherapy compared with those who had not. CONCLUSIONS: The feasibility of performing off-site in vitro drug resistance assays on resected malignant mesothelioma specimens is reported. A significant proportion of mesothelioma tumors exhibited extreme/intermediate resistance to cisplatin, gemcitabine, or vinorelbine.
Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Mesotelioma/tratamiento farmacológico , Neoplasias Pleurales/tratamiento farmacológico , Vinblastina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Estudios de Cohortes , Desoxicitidina/farmacología , Estudios de Factibilidad , Humanos , Mesotelioma/patología , Mesotelioma/cirugía , Persona de Mediana Edad , Terapia Neoadyuvante , Selección de Paciente , Neoplasias Pleurales/patología , Neoplasias Pleurales/cirugía , Factores de Tiempo , Células Tumorales Cultivadas , Vinblastina/farmacología , Vinorelbina , GemcitabinaRESUMEN
OBJECTIVE: We sought to prospectively determine the feasibility and safety of hyperthermic intraoperative intracavitary cisplatin perfusion immediately after extrapleural pneumonectomy in the treatment of malignant pleural mesothelioma. METHODS: Patients with malignant pleural mesothelioma who were surgical candidates underwent extrapleural pneumonectomy followed by hyperthermic intraoperative intracavitary cisplatin perfusion, consisting of a 1-hour lavage of the chest and abdomen with cisplatin (42 degrees C) at 225 mg/m(2). Pharmacologic cytoprotection consisted of intravenous sodium thiosulfate with or without amifostine. Morbidity and mortality were recorded prospectively. RESULTS: Ninety-six (79%) of 121 enrolled patients underwent extrapleural pneumonectomy, of whom 92 (76%) received hyperthermic intraoperative intracavitary cisplatin perfusion after extrapleural pneumonectomy. Fifty-three (58%) patients had epithelial tumors, and 39 (42%) had nonepithelial histology. Hospital mortality was 4.3%. Morbidity (grade 3 or 4, 49%) included atrial fibrillation in 22 (23.9%) patients, venous thrombosis in 12 (13%) patients, and laryngeal nerve dysfunction in 10 (11%) patients. Nine patients had renal toxicity, which was attributable to cisplatin in 8 of them. Among the 27 patients who also received amifostine (910 mg/m(2)), 1 patient had grade 3 renal toxicity attributable to cisplatin. Recurrence of malignant pleural mesothelioma was documented in 47 (51%) patients, with ipsilateral recurrence in 17.4% of patients. The median survival of the 121 enrolled patients was 12.8 months. CONCLUSIONS: Hyperthermic intraoperative intracavitary cisplatin perfusion following extrapleural pneumonectomy can be performed with acceptable morbidity and mortality. The use of amifostine in addition to sodium thiosulfate might reduce cisplatin-associated renal toxicity. Hyperthermic intraoperative intracavitary cisplatin perfusion following extrapleural pneumonectomy might enhance local control in the chest.
Asunto(s)
Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Cuidados Intraoperatorios , Mesotelioma/cirugía , Neoplasias Pleurales/cirugía , Neumonectomía , Adulto , Anciano , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Terapia Combinada , Femenino , Calor , Humanos , Riñón/efectos de los fármacos , Masculino , Mesotelioma/tratamiento farmacológico , Mesotelioma/mortalidad , Mesotelioma/secundario , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasias Pleurales/tratamiento farmacológico , Neoplasias Pleurales/mortalidad , Complicaciones Posoperatorias , Tasa de Supervivencia , Irrigación TerapéuticaRESUMEN
Malignant pleural mesothelioma is a uniformly fatal disease with a poor prognosis. Multimodality therapy, including macroscopic complete resection, chemotherapy and/or radiotherapy, has improved survival relative to historical controls, but local recurrence remains problematic. Novel strategies are needed to improve local control. Intracavitary chemotherapy (IC) can deliver higher doses of drug locally with less toxicity than corresponding systemic therapy. When combined with hyperthermia, there is also an increase in local drug absorption and cytotoxic effect. Several phase I and II clinical trials have shown IC to be safe and feasible. Our experience and technique of hyperthermic IC is described. The evolution of our experience has led to the use of pharmacologic renal cytoprotection, which has permitted the safe administration of higher doses of IC than previously described. Further trials are being performed with a multidrug combination following macroscopic complete resection.